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Jonathan M. Petrash, Muthenna Puppala, Jessica Ponder, P. Suryanarayana, G. B. Reddy, Daniel V. LaBarbera; Isolation And Characterization Of A Novel Aldose Reductase Inhibitor From Emblica officinalis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1055.
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The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans. Extracts from this plant have been shown to be efficacious against the progression of cataract in a diabetic rat model. The purpose of this study was to isolate a bioactive constituent from gooseberry that may be responsible for preventing the onset and progression of diabetic eye disease.
Aqueous extracted materials from E. officinalis were fractionated first by Sephadex LH-20 chromatography and subsequently by C-18 reverse phase HPLC. Purification was guided by assaying column fractions for aldose reductase inhibitor activity using the recombinant human enzyme (AKR1B1). Purified inhibitor was subjected to 1H and 13C NMR and LC-MS for structure determination. Inhibitor activity in organ culture was assessed by measuring suppression of sorbitol production in AKR1B1 transgenic mouse lenses incubated under high glucose conditions. Computational modeling was carried out with Discovery Studio software and Ligand Scout.
Structure elucidation by NMR and LC-MS identified β-glucogallin as the active inhibitor purified from E. officinalis. An IC50 of approximately 17 μM was determined in enzyme inhibition studies using glucose as an enzyme substrate. Virtually no inhibition was observed against AKR1A1 and ARK1B10, two major human aldo-keto reductases that are structurally related to AKR1B1. Favorable binding energies provided by multiple interactions indicates that β-glucogallin binds at both the "anionic" and "specificity" pockets at the active site of AKR1B1. Addition of 30 μM β-glucogallin reduced sorbitol accumulation by 73% in AKR1B1 transgenic lenses cultured in the presence of 27 mM glucose (P<0.05).
This study identifies β-glucogallin as a potent and selective aldose reductase inhibitor.
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